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The Association of Folic Acid Iron Nutrition Durin
The Association of Folic Acid Iron Nutrition Durin
The Association of Folic Acid Iron Nutrition Durin
Article
The Association of Folic Acid, Iron Nutrition during Pregnancy
and Congenital Heart Disease in Northwestern China:
A Matched Case-Control Study
Ming-Xin Yan 1 , Yan Zhao 2 , Dou-Dou Zhao 3 , Shao-Nong Dang 1 , Ruo Zhang 1 , Xin-Yu Duan 1 , Pei-Xi Rong 1 ,
Yu-Song Dang 1 , Lei-Lei Pei 1, * and Peng-Fei Qu 3, *
1 Department of Epidemiology and Biostatistics, School of Public Health, Xi’an Jiaotong University Health
Science Center, Xi’an 710061, China
2 Department of Dermatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
3 Translational Medicine Center, Northwest Women’s and Children’s Hospital, Xi’an 710061, China
* Correspondence: pll_paper@126.com (L.-L.P.); xinxi3057@163.com (P.-F.Q.)
Abstract: Background: The purpose of this study was to investigate the relationship between folic
acid and iron nutrition during pregnancy and congenital heart disease (CHD) in the offspring.
Methods: Conditional logistic regression models and nonlinear mixed-effects models were used to
analyze the effects of folic acid and iron nutrition during pregnancy on CHD in offspring. Results:
After adjusting for confounders, folic acid or iron supplementation during pregnancy reduced the
risk for fetal CHD (OR = 0.60 (0.45, 0.82) or 0.36 (0.27, 0.48)). Similarly, dietary iron intake during
pregnancy (≥29 mg/d) was associated with a reduced risk of fetal CHD (OR = 0.64 (0.46, 0.88)).
Additionally, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84))
Citation: Yan, M.-X.; Zhao, Y.;
or iron (OR = 0.32 (0.16, 0.60)), women who supplemented both folic acid and iron had lower
Zhao, D.-D.; Dang, S.-N.; Zhang, R.;
risk for newborns with CHD (OR = 0.22 (0.15, 0.34)). Similarly, compared with women who only
Duan, X.-Y.; Rong, P.-X.; Dang, Y.-S.;
Pei, L.-L.; Qu, P.-F. The Association of
supplemented folic acid (OR = 0.59 (0.41, 0.84)) or higher dietary iron intake (≥29 mg/d) (OR = 0.60
Folic Acid, Iron Nutrition during (0.33, 1.09)), women who supplemented both folic acid and higher dietary iron intake (≥29 mg/d) had
Pregnancy and Congenital Heart lower risk for the newborn with CHD (OR = 0.41 (0.28, 0.62)). The combined effects were significant
Disease in Northwestern China: in the multiplication model (OR = 0.35 (0.26, 0.48) or 0.66 (0.50, 0.85)) but not in the additive model.
A Matched Case-Control Study. Conclusions: Our study found that folic acid and iron nutrition during pregnancy were associated
Nutrients 2022, 14, 4541. https:// with a reduced risk of CHD in the offspring and confirmed a statistically significant multiplicative
doi.org/10.3390/nu14214541 interaction between folic acid and iron nutrition on the reduced risk of CHD in offspring.
Academic Editor: Gladys
Oluyemisi Latunde-Dada Keywords: congenital heart disease; folic acid; iron nutrition; interaction
their family numbers were surveyed when necessary to make the information obtained
as accurate as possible. Information on the birth of newborns and diagnosis of pregnancy
outcomes was collected by means of the hospital medical record. Experienced cardio-
vascular epidemiologists, obstetricians, pediatricians, and imaging physicians examined
the questionnaire and performed clinical diagnostics of cases and controls. The specific
diagnosis of CHD was made by qualified specialists based on a comprehensive analysis of
the medical history, symptoms, signs and ancillary tests, of which the specialized neonatal
echocardiogram and cardiovascular angiography were key points for confirming the CHD.
In addition, a follow-up telephone was also undertaken within one year after birth to
confirm the diagnoses.
No), alcohol consumption in pregnancy (Yes, No), passive smoking in pregnancy (Yes, No),
hair dyeing in pregnancy (Yes, No) and pregnancy frequency (1, ≥2).
Alcohol consumption included a variety of alcoholic beverages (e.g., white wine, beer,
red wine, etc.) during the whole pregnancy. Passive smoking was defined as inhaling
smoke for more than 15 min per day and at least one day per week during pregnancy; Hair
dyeing and perming was defined as dyeing or perming hair ≥ 1 time during pregnancy. We
used principal component analysis to construct a wealth index for measuring household
economic level, incorporating variables such as monthly household income, monthly
expenditure, housing type, household appliances, and transportation [28]. This wealth
index was divided into thirds as an indicator for the poor, medium, and rich households.
3. Results
3.1. Participants’ Characteristics
A total of 1800 subjects were included in this study, including 600 cases in the case
group and 1200 cases in the control group. The statistically significant differences in baseline
characteristics of mothers between the case and control group were found (Table 1), includ-
ing ethnicity, education, residence, wealth index, cold in early pregnancy, drinking, passive
smoke, hair dyeing and perming, and gravidity. There were no statistically significant
differences in maternal age and fever in early pregnancy between the two groups.
Nutrients 2022, 14, 4541 5 of 11
Table 1. Characteristics of participants in the case group and the control group.
Cases Controls
Variables χ2 p Value
(N = 600) (N = 1200)
Age, n (%) 3.085 0.079
<30 years 378 (63.00) 806 (67.17)
≥30 years 222 (37.00) 394 (32.83)
Ethnicity, n (%) 10.658 0.001
1192
Han 585 (97.50)
(99.33)
Other 15 (2.50) 8 (0.67)
Education, n (%) 88.615 <0.001
Senior high school or lower 264 (44.00) 270 (22.50)
College or above 336 (56.00) 930 (77.50)
Residence, n (%) 178.249 <0.001
Urban 201 (33.50) 800 (66.67)
Rural 399 (66.50) 400 (33.33)
Wealth index, n (%) 116.335 <0.001
Poor 313 (52.17) 331 (27.58)
Moderate 167 (27.83) 398 (33.17)
Rich 120 (20.00) 471 (39.25)
Cold in early pregnancy, n (%) 22.227 <0.001
No 415 (69.17) 951 (79.25)
Yes 185 (30.83) 249 (20.75)
Fever in early pregnancy, n (%) 3.161 0.075
1120
No 546 (91.00)
(93.33)
Yes 54 (9.00) 80 (6.67)
Drinking, n (%) 15.298 <0.001
1192
No 582 (97.00)
(99.33)
Yes 18 (3.00) 8 (0.67)
Passive smoke, n (%) 36.090 <0.001
No 255 (42.50) 690 (57.50)
Yes 345 (57.50) 510 (42.50)
Hair dyeing and perming, n (%) 13.292 <0.001
1168
No 563 (93.83)
(97.33)
Yes 37 (6.17) 32 (2.67)
Gravidity, n (%) 24.396 <0.001
1 236 (39.33) 620 (51.67)
≥2 364 (60.67) 580 (48.33)
Table 2. The association of maternal folic acid and iron nutrition during pregnancy with CHD.
Table 3. Interaction effect of maternal folic acid and iron nutrition on the occurrence of CHD.
Table 3. Cont.
Table 4. Multiplicative and additive interaction of maternal folic acid and iron nutrition in incidence
of CHD.
4. Discussion
Our study investigated the association of maternal folic acid and iron nutrition during
pregnancy with the risk of CHD in the offspring and explored the interaction of maternal
folic acid and iron nutrition in incidence of CHD, using a matched case-control design
in Northwest China. We have got two key findings. One, mothers who supplemented
with folic acid or iron during pregnancy reduced the risk of giving birth to newborns
with CHD. Similarly, more than 29 mg/d dietary intake of iron during pregnancy reduced
the risk of CHD in their offspring. Two, we also found the multiplicative interaction
of folic acid supplementation with iron supplementation in pregnancy concerning the
reduced risk of CHD in the offspring. Meanwhile, the multiplicative interaction of folic
acid supplementation and dietary iron intake in the incidence of CHD in the offspring was
Nutrients 2022, 14, 4541 8 of 11
also observed. However, the additive interaction of folic acid supplementation and iron
nutrition still needed to be confirmed. The sensitivity analysis of the study also showed
stable results.
First, maternal demand for nutrients gradually increases during pregnancy, but a
large number of women do not get enough nutrients during this period [13]. Due to fetal
development, in particular, women during pregnancy need 3–6 times higher folic acid than
those in the non-pregnant state. Xu et al. found that maternal folic acid supplementation
during pregnancy reduced the risk for CHD by 40% based on the meta-analysis [30].
In a Dutch case-control study, mothers who supplemented folic acid during pregnancy
had a reduced risk of fetuses with CHD [31]. A similar result from the birth cohort was
also obtained in China [32]. Studies in Canada have shown that during pregnancy, food
fortification with folic acid could lead to a 6% reduction in the type of severe CHD per
year [33]. Folic acid is an important carrier source in the metabolism of one-carbon units
in the body. When the body is deficient in folic acid, the body conserves one-carbon units
through regulatory mechanisms, which may lead to hyperhomocysteinemia [34]. A high
level of homocysteine is considered to be an independent risk factor for CHD, which in
turn affects embryonic heart development [34,35]. Our findings support the importance
of folic acid supplementation during pregnancy for the prevention of CHD in women of
childbearing age. Nevertheless, the association of dietary folic acid intake with CHD was
not confirmed yet.
Second, iron’s nutritional status also plays a key role in the development of the
cardiovascular system. In China, however, the prevalence of iron deficiency among women
of childbearing age is 49.6%, reaching 61.7% among pregnant women [36]. Previous
research found that iron deficiency can cause tissue hypoxia and stress response, which
can affect the normal development of the cardiovascular system [37]. It was reported that
maternal iron supplementation or higher dietary iron intake during pregnancy reduced the
risk of CHD in the fetus [38]. In animal experiments, iron deficiency was associated with
heart enlargement during the sensitive period of cardiovascular development in embryonic
rats [14]. A case-control study consisting of 410 CHD cases and 100 controls in China
found differences in iron levels between these two groups [39]. Our findings support the
importance of both iron supplementation and higher dietary iron intake during pregnancy
for the prevention of CHD in offspring.
Third, we determined the combined effect of maternal concomitant folic acid and
iron nutrition during pregnancy on the incidence of CHD in the offspring. After adjusting
for potential confounders, the multiplicative interaction of folic acid with iron nutrition
during pregnancy concerning the reduced risk of CHD in the offspring was significant. In
other words, folic acid administration and higher dietary iron intake during pregnancy
synergistically contributed to the lower incidence of CHD in the offspring. Previous studies
have found that folic acid supplementation and phenytoin therapy have a superimposed
effect on better seizure control [40]. Folic acid supplementation and RFC1 (GG) genotype
during pregnancy have gene-nutrition interactions on fetal neural tube defects (NTDs) [41].
The mechanism of action of folic acid and iron nutrition interacting with offspring CHD
may be complex. According to an animal study, the low iron status may alter the utilization
of folic acid despite adequate folic acid intake throughout the organism [42]. However,
further studies will be required to corroborate these findings and, if confirmed, to elucidate
possible reasons for these changes.
Our study is the first to explore the interaction between folic acid and iron nutrition
during pregnancy in the incidence of CHD in the offspring, providing valuable evidence
for the prevention of CHD in the future. However, some limitations of our study are
worth discussing. First, the information on dietary and non-dietary during pregnancy
was obtained through the mother’s own recall, which might lead to recall bias. Second,
the dietary information throughout pregnancy, rather than during the critical period of
fetal cardiac development (3–8 weeks of gestation) was recalled by mothers using FFQ.
However, studies have suggested that mothers have stable dietary patterns and nutritional
Nutrients 2022, 14, 4541 9 of 11
intake throughout pregnancy [18,19]. Third, due to the small sample size, we cannot
determine the additive interaction of folic acid and iron nutrition when interpreting our
results. Finally, these findings are based on case-control studies, and the causal relationship
between maternal folic acid and iron nutrition during pregnancy and CHD in the offspring
could not be demonstrated. Another large-sample population-based cohort study should
be established subsequently to confirm these relationships.
In conclusion, this study found that folic acid supplementation, iron supplements and
higher dietary iron intake during pregnancy reduced the risk of CHD. In particular, the
multiplicative interaction of folic acid supplementation and iron nutrition in the incidence
of CHD was confirmed, and these two nutrients synergistically contributed to the lower
incidence of CHD in the offspring. Therefore, from a maternal and child health perspective,
sufficient folic acid and iron nutrients during pregnancy would help to reduce fetal CHD.
Supplementary Materials: The following supporting information can be downloaded at: https://www.
mdpi.com/article/10.3390/nu14214541/s1, Table S1: Types of congenital heart disease; Table S2:
Interaction of maternal folic acid and iron nutrition in incidence of different subtypes of CHD;
Table S3: Multiplication and additive interaction of folic acid and iron nutrition in incidence of
different subtypes of CHD; Table S4: Interaction of folic acid and iron supplements in incidence of
CHD by different sociodemographic characteristics; Table S5: Multiplicative and additive interaction
indicators of folic acid and iron supplements in incidence of CHD by different sociodemographic
characteristics; Table S6: Interaction of maternal folic acid supplement and dietary iron intake
in incidence of CHD by different sociodemographic characteristics; Table S7: Multiplication and
additive interaction indicators of folic acid supplement and dietary iron intake on CHD by different
sociodemographic characteristics.
Author Contributions: M.-X.Y.: Writing—original draft. Y.Z.: Investigation, Project administration.
D.-D.Z.: Data curation, Investigation. S.-N.D.: Methodology, Investigation. R.Z.: Investigation.
X.-Y.D.: Investigation. P.-X.R.: Conceptualization, Supervision. Y.-S.D.: Conceptualization. L.-L.P.:
Data curation, Writing—review & editing. P.-F.Q.: Funding acquisition, Supervision, Writing—review
& editing. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the National Natural Science Foundation of China (grant
numbers 82103924, 72174167 and 81230016).
Institutional Review Board Statement: The study was in accordance with the guidelines of the
Declaration of Helsinki, and approved by the ethics committee of Xi’an Jiaotong University Health
Science Center (No. 2012008).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The data present in this study are available on request from the
corresponding authors.
Acknowledgments: The authors thank all medical staff involved in the study for recruiting the
participants. The authors also thank all mothers and infants who participated in the study and all
investigators who contributed to data collection.
Conflicts of Interest: The authors declare no conflict of interest.
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